Cutaneous administration system

ABSTRACT

Bioactive agents are cutaneously delivered by a jet dispenser using inkjet technology, such as that used in printing. The dispenser propels precise volumes of bioactive agent toward the skin, where they exert a local or topical effect, or move through the skin for transdermal systemic delivery. Drugs are either delivered directly to the skin, or are introduced into a transdermal patch, which may receive repeated dosages. A controller in the dispenser may control delivery of multiple different drugs, timing of drug administration, or change drug regimens in response to a changing medical condition of a patient, such as those monitored by a sensor in communication with the controller, for example to prevent an overdose. The dispenser may act as an electromechanical patch, capable of long term administration of drugs to the skin, to achieve local or systemic pharmaceutical effects. Administration methods are also provided, along with replacement kits.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 09/697,603 filed on Sep.28, 2001 now U.S Pat. No. 6,723,077 which is hereby incorporated byreference herein.

This invention relates generally to the administration of compositions(such as pharmaceutical compositions) for cutaneous administration,including transdermal absorption through the skin. In particular, thisinvention combines the previously unrelated technologies ofpharmaceutical administration and inkjet technology.

Pharmaceutical compositions provide effective treatments for a varietyof illnesses. Unfortunately, there are many obstacles to theadministration of therapeutically effective doses of many medications.For example, some drugs (particularly peptide based drugs such asinsulin) are partially or totally inactivated following oral ingestion,by the highly acidic environment of the stomach. Another problem is the“first pass” effect, which refers to the partial inactivation of orallyingested drugs in the liver, after they have been absorbed from thegastrointestinal system, but before they have exerted their fulltherapeutic effect. Even when these problems are overcome, patientsoften fail to take their medications at the proper prescribed intervals,or for the necessary period of time, to achieve an optimal therapeuticresponse.

Inhalational and intranasal administration have been used as alternativeroutes of drug delivery. Inhaled drugs can be absorbed directly throughthe mucous membranes and epithelium of the respiratory tract, therebyminimizing initial inactivation of bioactive substances by the liver.Inhalational delivery can also provide drugs directly to therapeuticsites of action (such as the lungs or the sinuses). This mode ofadministration has been particularly effective for the delivery ofpulmonary drugs (such as asthma medications) and peptide based drugs(usually via intranasal administration), using metered dose inhalers(MDIs). However, MDIs often require coordinating inspiration withactuation of the MDI, and some patients are not able to master thistechnique. Moreover, patients still often forget to take the medicationat prescribed times, or for the necessary period of time to achieveclinical goals. Other patients inadvertently or inappropriately usemedications, leading to hospitalizations, morbidity, and even death.

In an effort to overcome such problems, some drugs are administered bypassive cutaneous routes, such as transdermal delivery of drugs from apatch applied to the skin. Examples of drugs that are routinelyadministered by this route are nitroglycerin, steroid hormones, and someanalgesics (such as fentanyl). Transdermal administration avoids initialinactivation of drugs in the gastrointestinal tract, and providescontinuous dosages usually over a relatively short period of time (suchas a day), without requiring active participation by the patient.Continuous sustained administration provides better bioavailability ofthe drug, without peaks and troughs, and eliminates the problem of thepatient forgetting to take multiple doses of the drug throughout theday. However the patch must be changed regularly, usually each day, toprovide a necessary drug concentration in the patch to establish thecorrect concentration gradient for delivery of the appropriate dose ofthe drug across the skin.

In addition to transdermal systemic delivery of drugs, topical deliveryof drugs to the surface of the skin is also used for treating many skinconditions. For example, antibiotics are topically administered to theskin to treat infection, anesthetics to treat pain, retinoids to treatacne, and minoxidil to treat hair loss. These drugs must be repeatedlyapplied to the skin to achieve their effect, and much of the dosage maybe lost by drainage of liquid from the application site, or beinginadvertently wiped away. Moreover, excess drug is usually applied tothe skin, which can lead to undesired toxic effects particularly if thedrug is absorbed through the skin.

Devices and methods are disclosed herein for improving the cutaneousdelivery of drugs, by using inkjet-like applicators for transdermal andother cutaneous delivery of drugs. Kits and systems for administratingdrugs in this fashion are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective, fragmented, and partially schematic, view ofone form of a transdermal application system illustrated herein, havinga dispenser and a transdermal patch applied to a human arm.

FIG. 2 is an enlarged, side elevational view of the transdermalapplication system of FIG. 1, shown in place over a transdermal patchfor dispensing.

FIG. 3 is an enlarged, front elevational view of the dispenser of FIG.1, showing a container module removed from the applicator and aprotective cap for placement on the droplet head during periods ofinactivity. This figure also schematically illustrates how theapplicator may be connected to a remote control device, such as acomputer.

FIG. 4 is a top plan view of another form of a transdermal patch, whichmay be used in conjunction with the transdermal application system ofFIG. 1.

FIG. 5 is a perspective, fragmented, and partially schematic, view of amore compact alternative form of a transdermal application systemillustrated herein, having a compact dispenser which may be used with orwithout a patch, here shown retained against a human arm.

FIG. 6 is a cross-sectional, side elevational view of a removable moduleof the dispenser of FIG. 5.

FIG. 7 is a bottom plan view of the module of FIG. 7.

FIG. 8 is a schematic view, partially in cross-section, of analternative embodiment, in which a bioactive agent is administered froma thermal jet dispenser to a cutaneous target, such as a pad, acting asa substitute for conventional intravenous (“IV”) administration of thebioactive agent.

FIG. 9 is a side elevational view, partially in cross-section, of thetransdermal application system of FIG. 5, taken along lines 9-9 thereof,showing application of a bioactive-composition-attracting agent, such asa cream, a paste, or a salve to the skin, here on a skin blemish, suchas a wart.

DETAILED DESCRIPTION OF PARTICULAR EXAMPLES

Unless otherwise noted, technical terms are used according toconventional usage. Definitions of common terms in pharmacology may befound in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, published by Mack Publishing Company, 1995 (ISBN0-912734-04-3). Transdermal delivery is discussed in particular at page743 and pages 1577-1584.

The singular forms “a,” “an,” and “the” refer to one or more than one,unless the context clearly dictates otherwise. The term “comprising”means “including.”

An “array” refers to a predetermined pattern, which can be eitherregular or irregular. Examples of arrays are linear distributions ortwo-dimensional matrices.

A “bioactive” composition, substance or agent is a composition whichaffects a biological function of a subject to which it is administered.An example of a bioactive composition is a pharmaceutical substance,such as a drug, which is given to a subject to alter physiologicalcondition of the subject, such as a disease. Bioactive substances,compositions and agents also include other biomolecules, such asproteins and nucleic acids, or liposomes and other carrier vehicles thatcontain bioactive substances.

“Cutaneous” refers to the skin, and “cutaneous delivery” meansapplication to the skin. This form of delivery can include eitherdelivery to the surface of the skin to provide a local or topicaleffect, or transdermal delivery, in which a drug diffuses through theskin surface and into the underlying microvasculature, often forsystemic administration of the drug.

The present disclosure concerns an applicator for cutaneous delivery ofa bioactive composition using a jet dispenser, such as a piezoelectricor thermal jet dispenser, for instance of a construction used in theinkjet printing arts. The dispenser includes a container for holding thebioactive agent and delivering it to a dispenser orifice, or an array ofdispenser orifices. The thermal or piezoelectric jet propels preciseamounts of droplets from the dispenser toward a cutaneous target. In oneembodiment, a spacer is also provided between the dispenser orifice anda cutaneous target, to space the dispenser a desired distance away fromthe cutaneous target during delivery of the bioactive agent. This spacermay be attached to either the skin or the dispenser, or merely beinterposed between them, to provide an interface across which thebioactive substance may be distributed from the orifice, or from anarray of orifices, to a cutaneous target. The target may include skin ora skin patch, such as a transdermal drug delivery patch, which acts as areservoir for subsequent prolonged transdermal delivery of the agent.

In certain embodiments, the dispenser includes the bioactive agent inthe container. Examples of agents that can be included in the containerinclude pharmaceutical compositions that are capable of transdermaldelivery. Such agents include drugs having sufficient lipophilicity orhydrophilicity to move through the skin surface and stratum corneum.Certain of these agents are designed to reach the microvasculature ofthe skin, for subsequent systemic absorption and distribution. Examplesof agents that are suitable for transdermal delivery includescopolamine, nitrates such as nitroglycerine, an antihypertensive oranti-adrenergic drug such as clonidine, steroid hormones such as17-beta-estradiol and testosterone, analgesics, such as the opioidanalgesic fentanyl, and treatments for nicotine withdrawal, such asnicotine. Many analogues of these drugs retain their biologicalactivity, and are also suitable for transdermal delivery. Although thedisclosed dispenser is particularly suited for transdermal delivery ofdrugs, it can also be used for topical surface application of drugs,such as antibiotics, corticosteroids, minoxidil or retinoids (such asRetin A).

The dispenser may also include a controller for manually orautomatically dispensing the bioactive substance from the dispenser atselected times. The controller may take the form of an actuator that ismanually depressed to activate the dispenser and dispense the agent.Alternatively, the controller may be a microprocessor which isprogrammed to dispense the bioactive substance at predeterminedintervals, for example several times a day, directly on to the skin oron to a patch. Alternatively, the controller can be used to adjustdosages of drug administered, for example for a particular time of day,an event (such as an activity that will require a dosage modification),or detection of a physiological condition (such a an adverse drugreaction that requires reduction or cessation of drug administration).When the dispenser is used with a patch, the dispenser may be used torecharge the patch and avoid the necessity of changing the patch asoften. Either with or without a patch, complex administration protocolsmay be followed, for example applying different drugs at different timesthroughout the day or longer period, for example as long as a week, amonth, or even longer.

In certain examples, the container may carry multiple container modules,such as removable and replaceable modules that contain the bioactiveagent(s). Several modules may contain the same or different agents, forexample different agents that combine before or at the time of deliveryto modify one or both of the agents, or to produce a desired bioactiveeffect. An example of a modifying substance that may be combined at thepoint of ejection is a penetration enhancer that improves cutaneouspenetration of the other bioactive substance. Penetration enhancers thatmay be mixed with a bioactive agent at the time of delivery includesolvents such as water; alcohols (such as methanol, ethanol and2-propanol); alkyl methyl sulfoxides (such as dimethyl sulfoxide,decylmethyl sulfoxide and tetradecylmethyl sulfoxide); pyrrolidones(such as 2-pyrrolidone, N-methyl-2-pyrroloidone andN-(2-hydroxyethyl)pyrrolidone); laurocapram; and miscellaneous solventssuch as acetone, dimethyl acetamide, dimethyl formamide, andtetrahyrdofurfuryl alcohol. Other penetration enhancers includeamphiphiles such as L-amino acids, anionic surfactants, cationicsurfactants, amphoteric surfactants, nonionic surfactants, fatty acidsand alcohols. Additional penetration enhancers are disclosed inRemington: The Science and Practice of Pharmacy, 19^(th) Edition (1995)on page 1583. Of course agents such as penetration enhancers can also bepremixed with the bioactive agent prior to the point of ejection, forexample the bioactive agent and modifying substance can be presenttogether in the container.

The bioactive agent may be any flowable fluid (for example a liquid, gelor powder), although liquids are particularly of use in the dispenser.In some embodiments, at least one of the container modules may contain abioactive agent in powder or other dry form. The powder or other agentis dispensed from the container, and may be combined with a liquid (suchas a penetration enhancer) en route to the cutaneous delivery site. Theinterface provided by a spacer between the orifice plate and the targetallows chemical reactions to occur, as well as phase changes tostabilize (such as a change from a solid to a liquid state). Thisinterface may also provide flexibility in the distribution of the drugacross a larger target area, as compared to application of the agentfrom an orifice that abuts the target. Using existing inkjet technology,distribution of the drug to the target may be carefully controlled, andexact dosing of the drug may be achieved. Controllers may be used todispense simple or complex drug regimens, which is of particularadvantage in patients who require numerous daily medications.Computerized control of medication dosing, which may be programmed bymedical personnel for subsequent automated delivery, can help avoidtoxic drug interactions, overdosages, and deaths.

The applicator is suitable for use in a variety of ways. For example,the applicator may be intermittently applied to the skin to administer adosage of a drug directly to the skin. Alternatively, the applicator maybe applied to a transdermal patch to recharge it with medication,instead of replacing the patch. In another embodiment, the applicatormay be selectively retained in prolonged contact with the cutaneoustarget, for example by securing the applicator to the skin with anattachment member, such as a strap or adhesive. In this manner, theactive agent may be administered from the dispenser for a prolongedperiod of time into a transdermal patch, or directly onto the skin. Areplaceable container module may be removed from the applicator andreplaced, to avoid the necessity of removing the applicator from thepatient.

In some embodiments, the applicator forms a substantially sealed chamberdirectly against the skin, without an intervening transdermal patch, andeffectively become a direct cutaneous or transdermal applicator. Inparticularly effective embodiments, an elastomeric seal (such as acontinuous seal) is provided between the applicator and the skin to formthe sealed chamber in which the drug can be maintained until it isabsorbed. Conditions in the sealed chamber may be altered to enhanceabsorption of the drug, for example by increasing humidity in thechamber by dispensing water droplets, or intermittently applying apenetration enhancer to the skin from the dispenser.

One particularly disclosed embodiment of the device includes apiezoelectric or thermal jet dispenser that includes a plurality ofremovable modules in fluid communication with one or more fluid orifices(such as an array of orifices) ejecting and directing a pharmaceuticalfluid from the modules toward a cutaneous target. A spacer may becarried by the dispenser and positioned to be disposed against thecutaneous target while the dispenser ejects the pharmaceutical fluidfrom the dispenser. A programmable microprocessor in the dispenser maycontrol ejection of the pharmaceutical fluid from the orifice plate atpre-selected intervals, such as every three or four hours, or even everyfew minutes or seconds, or ejection can be triggered by a sensor orother feedback mechanism.

The device may further include a programming module, such as a keyboardfor entering dosage information, a display screen for showing whatinformation has been entered, and indicators (such as one or more lightsor a display screen on the exterior of the device) that provideinformation about how much drug remains in the device. Display screensmay also provide information about medications in the device, andprovide an interface through which other information about themedications or their administration can be entered and/or obtained.

The following detailed description of the device is illustrated in theaccompanying figures.

Embodiment of FIGS. 1-3

The medication dispensers disclosed herein may be similar to liquiddispensers known as inkjet printheads used in inkjet printingmechanisms, such as printers, plotters, facsimile machines and the like,some of which are described for example in Durbeck and Sherr, OutputHardcopy Devices, Academic Press Inc., 1987 (ISBN 0-12-225040-0),particularly in chapter 13, pages 311-370. These technologies have incommon the extraction of small quantities of a fluid from a reservoir,which are converted into fine droplets, and transported through the airto a target medium by appropriate application of physical forces. Thistechnology has been implemented in a variety of ways, but one of thecommon approaches has been thermal inkjet technology, in which liquidsare heated using resistors to form drops and propel them from a chamberthrough an orifice toward a target. Another approach is piezoelectricinkjet technology, in which movement of a piezoelectric transducerchanges a chamber volume to generate the drop. An additional approach isknown as silicon electrostatic actuator (“SEA”) inkjet technology, suchas that disclosed in U.S. Pat. No. 5,739,831 to Nakamura (assigned toSeiko Epson Corporation).

A typical jet printing mechanism uses cartridges (often called “pens”)which shoot drops of liquid colorant (generally referred to as “ink”)onto a page. Each cartridge has a printhead formed with very smallnozzles through which the ink drops are fired. Most often, the printheadis held in a carriage which slides back and forth along a guide rod in areciprocating printhead system, with a target or print media, such aspaper, being advanced in steps between each pass of the printhead. Toprint an image on media, the printhead is scanned back and forth acrossthe page, shooting drops of ink in a desired pattern as it moves. Otherprinting systems known as “page-wide array” printers, extend theprinthead across the entire page in a stationary location, and print asthe media advances under the printhead. The particular liquid ejectionmechanism within either type of printhead may take on a variety ofdifferent forms known to those skilled in the art, such as thepiezoelectric or thermal printhead technology.

For instance two thermal ink ejection mechanisms are shown in U.S. Pat.Nos. 5,278,584 and 4,683,481, both assigned to the present assignee,Hewlet-Packard Company. In a thermal system, a barrier layer containingfluid channels and vaporization chambers is located between a nozzleorifice plate and a substrate layer. The substrate layer typicallycontains linear arrays of heater elements, such as resistors, which areenergized to heat ink within the vaporization chambers. Upon heating, anink droplet is ejected from a nozzle associated with the energizedresistor. By selectively energizing the resistors as the printhead movesacross the page, the ink is expelled in a pattern on the print media toform a desired image (e.g., picture, chart or text).

In piezoelectric inkjet technology, an activating pulse is applied to apiezoelectric plate or member attached to a plate, which then respondsby flexing to propel an ink drop out of a nozzle. Several examples ofpiezoelectric inkjet printheads are described in U.S. Pat. Nos.4,992,808; 6,186,619; and 6,149,968 (assigned to Xaar Technology Ltd.)and U.S. Pat. No. 6,193,343 and WO 00/16981 (assigned to Seiko EpsonCorporation).

Some printhead designs use “snapper” reservoir systems, in whichpermanent or semi-permanent printheads are used in conjunction with adetachable reservoir carrying a fresh liquid supply, with the reservoirbeing snapped into place on the printhead. Another design uses permanentor semi-permanent printheads in what is known in the industry as an“off-axis” printer. In an off-axis system, the printheads carry only asmall liquid supply reciprocally back and forth across the printzone,with this on-board supply being replenished through tubing that deliversliquid from an “off-axis main reservoir” placed at a remote, stationarylocation within or near the printhead. In both the snapper and off-axissystems, rather than purchasing an entire new cartridge which includes acostly new printhead, the consumer buys only a new supply of liquid forthe main reservoir.

In striving to duplicate the quality of photographic film images, theinkjet industry has focused on decreasing the size of ink dropletsejected from the nozzles, as well as accurately placing these dropletson the print media. For instance, some of the more recent inkjet printcartridges are able to deliver droplets of a size on the order of 0.5-6picoliters, although larger droplets can also be generated, for exampledroplets of 10, 50, 100 or more picoliters. The resolution within whichcurrently commercially available inkjet printing mechanisms may placeink droplets on a page is on the order of 1200-4800 dots per inch (knownin the industry as a “dpi” rating). Thus, while striving to achievephotographic print quality, inkjet printing technology has become veryadept at accurately metering and dispensing fluids. The ability todispense very small and accurate amounts of fluids (including liquidsand powders) is taken advantage of in constructing the transdermalcutaneous application systems illustrated herein.

While these inkjet printheads may be used in the cutaneous applicationsystems illustrated here, rather than using a printing analogy, theprinthead will instead be referred to in a more general nature as a“dispenser head” or “applicator head.”

FIGS. 1-3 illustrate one embodiment of a transdermal application system20, constructed in accordance with the present invention, for applying abioactive substance to a subject, such as to a forearm of an animal orperson 22, through the skin 24. While the bioactive agent, which istypically dispensed as a fluid, may be applied directly to skin 24, theillustrated embodiment shows applying the agent to an absorbent member,such as a patch 25 of a fabric or other absorbent material which isadhered to skin 24. Patch 25 has an upper exposed surface 26, and anopposing under surface 27 which is in contact with skin 24. A removableprotective layer 28, such as a layer of a liquid impermeable thinpolyester, may be selectively removed and reapplied to patch 25. In oneparticular embodiment, the fluid is applied to patch 25, which thenallows skin 24 to gradually absorb the fluid from patch 25.

Any of the many types of transdermal patches may be used, or modifiedfor use with the dispenser. For example the Testoderm® transdermalsystem (Alza Pharmaceuticals) uses a flexible backing of transparentpolyester, and a testosterone containing film of ethylene-vinyl acetatecopolymer membrane that contacts the skin surface and controls the rateof release of active agent from the system. The surface of the drugcontaining film is partially covered by thin adhesive stripes ofpolyisobutylene and colloidal silicon dioxide, to retain the drug filmin prolonged contact with the skin. In the present system, adhesive canbe provided on both surfaces of the drug containing film, for example onboth upper face 26 and under face 27 of patch 25, so that the flexiblepolyester backing 28 may be selectively removed to provide access to thedrug-containing layer without removing the patch. An adhesive releaselayer with openings in it can be provided between the patch and backing28, to help protect upper face 26 of patch 25 during repeated removalsof backing 28. Alternatively, the patch may be removed, recharged withthe drug, and then reapplied, in which event the impermeable backing 28may be permanently applied to patch 25. In this case, adhesive need onlybe present on under surface 27 of patch 25. In yet other embodiments,there may be no impermeable backing, such as layer 28, over patch 25,so, for instance the selected drug may be continually administered, orthe absorbency of the patch is sufficient to retain the drug in thepatch without an impermeable backing. Further examples of transdermalpatches that may be used or modified for use in the present system andmethod include the Nicoderm® and Duragesic® patch.

The transdermal application system 20 illustrated in FIG. 1 includes anapplicator or dispenser 30, which is illustrated as an applicator fordispensing a fluidic chemical composition either directly to skin 24, orto patch 25. The applicator 30 includes a main body 32 which may becoupled to a rectangular application head 34 via a linkage, such as ahollow ball and socket linkage 35 which allows applicator head 34 topivot with respect to main body 32. To assure even and controlledapplication of a chemical composition to skin 24 or patch 25, theillustrated applicator head 34 is provided with a pair of spacer bars 36and 38 at opposing edges of applicator head 34. Alternatively, a seriesof discrete spacer protrusions or bumps, or roller or wheel assemblies(not shown) may be used. As further alternative embodiments, one or morespacers may be formed on the patch 25, or a separate spacer unit (notshown) may be positioned between the dispenser head 34 and the patchupper surface 26 during delivery of the bioactive agent. While theillustrated applicator 30 includes a separate body 32 and applicatorhead 34, it is apparent that in some embodiments a simpler design mayeliminate linkage 35, such that the applicator is a one-piece member.

As shown in FIG. 3, applicator head 34 includes one or more ejectionheads, such as fluid ejection heads 40, 42, 44 and 46. Ejection heads40-46 may be constructed according to principles in the thermal inkjettechnology, using piezoelectric ejection techniques, or other manners offluid ejection known to those skilled in the inkjet arts. Indeed, theejection of some chemicals may be benefited by a thermal ink ejectiontechnology, in which elevated temperature can activate the agent. Incontrast, other agents may chemically degrade and lose some or allbioactivity when heated in a thermal system, and such compositions wouldpreferably be dispensed using a piezoelectric or other non-thermalejecting head technology. Preferably, the spacer bars 36, 38 maintain aspacing between the ejection heads 40-46 and the upper exposed surface26 of the patch 25 or skin 24 of greater than about 30 mil (30×10⁻³inch), for example 1-3 mm, or even 3-5 mm or more. One preferred spacingof 0.2-2.0 mm after the patch has swollen from soaking up the appliedfluid permits a smooth even application of fluid over patch 25.Additionally, this ejection head to receiving surface spacingadvantageously protects ejection heads 40-46 from unnecessarily cominginto contact with the patch 25, which avoids forcing fibers or otherdebris from the surface of the patch into the printhead nozzles.Adequate spacing between the nozzles and patch also avoids capillarywicking of drug from the nozzles, than can result in inadvertent orunwanted administration of drug to the patch. Such debris or otherfibers in the nozzles could potentially damage the ejection headnozzles, leading to fully or partially blocked nozzles that dispenseless fluid th an intended. Such debris could also lead to misdirecteddroplets which would miss the target area on patch 25. Applicator head34 may also include a feedback mechanism, for instance such as amechanical sensor or an optical sensor 48 which may be used byapplicator 30 in a closed-loop system, as described further below.

The fluid dispensed by ejection heads 40, 42, 44 and 46 may be stored inreplaceable fluid reservoirs 50, 52, 54 and 56, respectively. As shownin the specific example of FIG. 3, the reservoirs 50-56 may be insertedinto receptacles formed within main body 32. Following insertion of thereservoirs 50-56 into the main body 32, a multi-conduit fluid tubingsystem 58 delivers fluid from the reservoirs 50-56, through the hollowball and socket linkage 35, into applicator head 34. As shown in FIG. 3,a multi-conduit system 58 may include four discrete fluid conduits, suchas tubing running through applicator head 34, or conduits molded, boredor otherwise formed therein, such as conduits 60, 62, 64 and 66. In theillustrated embodiment, the conduits 60, 62, 64 and 66 deliver fluidfrom the respective reservoirs 50, 52, 54 and 56 to their respectiveassociated ejection heads 40, 42, 44 and 46.

To maintain ejection heads 40-46 relatively moist and free of clogsduring periods of applicator inactivity, the application system 20 mayinclude a protective ejection head storage and/or servicing member 68,which in the illustrated embodiment is rectangularly shaped to mate withthe open face of rectangular application head 34. Head storage member 68has four ejection head sealing members, for example elastomeric or foamcaps 70, 72, 74 and 76, which are positioned to seal ejection heads 40,42, 44 and 46 respectively, for instance, using various printhead capdesigns known to those skilled in the inkjet arts. To maintain caps70-76 against their respective ejection heads 40-46, the storage member68 may include a securement means, such as a pair of clips 78 that matewith applicator head 34 to selectively connect member 68 to applicatorhead 34.

In a more sophisticated embodiment, storage member 68 may also includeone or more ejection head wipers, such as elastomeric wipers 80, 82, 84and 86. In one embodiment of the storage member 68 having only caps70-76, the storage member 68 may be positioned over applicator head 34by movement in a direction parallel with the Z-axis, with securementmember 78 being formed with a snap-fit feature to hold member 68securely in place, with each of the ejection heads 40-46 restingsecurely against their respective caps 70-76. Such a capping systemhaving foam caps may be constructed as described in U.S. Pat. No.5,635,965 currently assigned to the Hewlett-Packard Company. A moresophisticated combination storage and servicing member 68 may havesecurement member 78 formed so that member 68 is applied over theapplicator head 34 in a direction parallel to the negative Y axis, andremoved in a direction parallel to the positive Y axis. Such a lateralapplication of the storage and service member 68 over applicator head 34allows elastomeric wipers 80-86 to wipe liquid or other residue fromejection heads 40-46 as member 68 is applied, as well as upon removal ofthe service member after uncapping. When the storage/service member 68has wiping capability, it may be desirable to have a back wall portion88 of the service member hinged or otherwise retractable to folddownwardly, so upon installation of member 68 the heads 40-46 firstcontact wiper blades 80-86, and upon removal of member 68, the lastitems which contact the heads 40-46 are the wipers 80-86.

As illustrated in FIG. 1, the applicator 30 includes an onboard ejectionhead controller 100, illustrated schematically for convenience.Controller 100 and ejection heads 40-46 receive power either from anonboard battery storage system, which may be located in either main body32, applicator head 34, or both. Alternatively, power may be suppliedfrom an external source, such as a standard electrical outlet. Ofcourse, rechargeable or replaceable batteries may be preferred in someembodiments for ease of portability and use. Controller 100 operates toapply firing signals to the ejection heads 40-46, which respond byejecting fluid from reservoirs 50-56, respectively. In a simpleembodiment, applicator 30 may include an ON/OFF power switch 102, towhich controller 100 responds by beginning and/or ending a fluidejection sequence. Alternatively, switch 102 may simply serve as an ONswitch, with controller 100 determining the precise amount of fluid tobe ejected from heads 40-46, and then stopping ejection automaticallyafter the selected metered amount has been dispensed.

In a more sophisticated embodiment, applicator 30 may include an inputkeypad 104, such as an alpha or alpha numeric keypad. Using keypad 104,a physician, nurse, pharmacist or other health professional, or thesubject 22 to which the fluid will be applied, may input variations inthe amount of and types of fluids dispensed by applicator head 34.Applicator 30 may also include a display screen, such as liquid crystaldisplay 105, to indicate which selections have been made using keypad104. Alternatively, keypad 104 may be eliminated, and the controller 100programmed to display various selections on screen 105. Use of a pair ofscrolling buttons 106 and 108 may allow different instructions orselections to be scrolled across, or up and down along, screen 105,including such information such as desired dosages, frequency, andpotential side effects.

Display screen 105 may also indicate various selections along an upperportion of the screen, adjacent buttons 102, 110 and/or 112, allowing auser to then select a particular drug or dosage by depressing one ormore of these buttons. Alternatively, depressing one of the buttonscould indicate the occurrence of a particular event, such as an adversemedication response that would alter (for example decrease) a subsequentdosage administration, or an event (such as physical exertion) than cansignal a need to alter a medication dosage. The controller can also beprogrammed to prevent unauthorized alteration of dosages, for example anincrease in a dosage of a controlled substance above that authorized bythe prescribing physician. Alternatively, the controller can permitcertain ranges of dosages to be administered, for example various dosesof an opioid pain reliever in response to fluctuating pain.

As shown in FIG. 3, a more expedient method of initially programmingcontroller 100, or supplying dosage and other information, may be to usea computer input conductor 114, selectively attachable to a receptacleon main body 32, to couple an external computer, microcomputer or otherinput device 115 to controller 100. It is apparent that other linkagedevices may be used to communicate between external computing device 115and controller 100, such as by using infrared signals, radio waves,modems, and the like. For example, a patient can download informationstored in the device about self-regulated dosage administrations orsymptoms experienced (as indicated for example by which buttons havebeen depressed on the device, and/or the pattern and frequency of thebuttons that are pushed). This information can be transmitted over amodem to a physician's or other health care provider's office, where itcan be displayed (in electronic or other form) to a health careprofessional, and appropriate action can be taken. For example, ifsymptoms are noted to be increasing in spite of administration of atherapeutic amount of a particular drug, consideration can be given toproviding a new drug or reconsidering the diagnosis for which the drughas been administered.

Alternatively, as shown in FIG. 2, main body 32 may define an input slot116 which is sized to receive an input device, such as a flash memorycard 118, which carries input data for controller 100. Indeed, use ofthe flash memory card 118 in conjunction with the controller 100 mayresult in the only other input device of applicator 30 being the ON/OFFswitch 102. Alternatively, the switch may only be an ON switch, with thecontroller 100 ceasing fluid application after a selected dosage hasbeen administered.

Thus, in one embodiment applicator 30 may only have an ON switch 102,and be completely preprogrammed via an external computer 115, such as ata doctor's office or pharmacy, prior to giving the applicator 30 to apatient. In another embodiment, the applicator 30 may be sold with onlyan ON switch 102, and with the physician or pharmacy supplying one ormore of the fluid reservoirs 50-56 in a kit with a flash memory card118. In such an example, the kit includes one or more reservoirs 50-56,a flash memory card 118, and may also include a supply of patches 25, orthe patches may be purchased separately. Alternatively, any combinationof the components can be provided in the kit.

While each of the fluid reservoirs 50-56 may carry different bioactiveagents, it may also be convenient to have each reservoir carry the sameagent, with controller 100 applying fluid from first reservoir 50 untilempty, followed by fluid from a second reservoir 52, and so forth. Insuch a same-fluid embodiment, it would be preferable for applicator 30to indicate to the person 22, or an attendant, when fluid is beingdispensed from the last reservoir, such as reservoir 56. This indicationmay take the form of displaying a message on screen 105, or simply byhaving an indicator light or a series of indicator lights mounted on themain body 32. For example, switch 102 may be back lighted to turn a redcolor when the supply of active agent in the containers 50-56 is low.Alternatively, the indicator may be an audible signal, such as a beepingsound or a buzzer, or a tactile signal, such as a vibratory or vibratingsignal similar to those used on pager devices.

As mentioned briefly above, applicator head 34 may also include anoptical sensor 48 constructed to have a variety of different uses. Forexample, optical sensor 48 may be able to determine whether thestorage/service member 68 is in place protecting applicator head 34.When so engaged, it may be practical for the controller 100 toperiodically purge fluid from the ejection heads 40-46, to keep the caps70-76 moist and to purge any blockages of dried or partially dryingfluid from the ejection head nozzles, or to prevent any inadvertent orundesired administration of the bioactive agent. Additionally, opticalsensor 48 may indicate to controller 100 whether ejection heads 40-46are located over bare skin 24, or over the exposed surface 26 of patch25. In some embodiments, to distinguish patch 25 from clothing or otherfabric, patch 25 has its exposed surface 26 treated with a visualindicator, such as a coating of infrared or ultraviolet ink which isdetectable by the sensor 48.

Embodiment f FIG. 4

Furthermore, the optical sensor 48 may be used in conjunction with asegmented pad 120 shown in FIG. 4. The pad 120 is divided into regions,here shown as four regions 122, 124, 126 and 128, separated from oneanother by a non-absorbing region 130, shown in this symmetricalembodiment as a plus (+) sign. Each of the four absorbent regions 122,124, 126 and 128 has an identifying indicia 132, 134, 136 and 138,respectively. The patch 120 may be covered with a moisture imperviouslayer, such as layer 28 described above. The optical sensor 48 may beused to recognize various identifying indicia 132-138, and apply aselected corresponding fluid from one of reservoirs 50-56 to a selectedregion 122-128 associated with each of indicia 132-138. For instance,optical sensors which can distinguish the colors of black, cyan, magentaand yellow from one another are disclosed in U.S. Pat. No. 6,036,298.Each of the indicia 132-138 may be a different one of these colors, andcontroller 100 recognizes each of the different indicia, and dispenses acorresponding fluid agent from ejection heads 40, 42, 44 or 46 to aselected area of the patch associated with the appropriate color.Moreover, if a tint, pigment or other colorant is added to the fluids inreservoirs 50-56, optical sensor 48 may be used to distinguish whichagent has previously been applied by applicator 30 to patch 120,allowing the controller to apply more of the same fluid over this area,a different fluid over another area, or no fluid over previously appliedareas. Alternatively, changes in color of the substrate may be sensed byoptical sensor 48 as a drug leaves patch 120, and this color change maybe used to indicate to the controller 100 that additional drug must bedispensed to patch 120.

In some embodiments of patch 120, such as shown in FIG. 4, patch 120 maybe constructed of a non-woven material which has selected regions whichmay be made absorbent, and other regions which may be madenon-absorbent. In the illustrated example, patch 120 is divided intofour absorbent quadrants 122, 124, 126 and 128 by the non-absorbentborder region 130. While a circular patch is illustrated, it is apparentthat the patch 120 may have other shapes, and each of the regions122-128 need not be symmetrical, but may be of differing sizes and/orshapes. One manner of making absorbent and non-absorbent regions in thenon-woven fabric arts is to form pad 120 as a multi-layer pad, with thelayers bonded together by applying heat along the border region 130.Typically non-woven fabrics, such as those of polyethylene andpolyurethane, are moisture impervious when manufactured, with moisturepervious or absorbent regions being formed by applying surfactants inregions 122, 124, 126 and 128.

It may be preferable in some embodiments to provide various indicia ormarkings on pad 120, such as indicia 132, 134, 136 and 138 appearingwithin the absorbent quadrants 122, 124, 126 and 128, respectively.Indicia 132-138 may be fashioned to change color after administration ofthe bioactive agent to the pad 120. Thus, a user of a single agentsystem may apply the agent at different times of the day. Rather thancontinually tearing off a depleted patch and replacing it with a newone, a situation which may be bothersome, time consuming and irritatingor painful, a single patch 120 may be used throughout the day, withfluid applied at various intervals (such as prescribed intervals) to thedifferent quadrants 122-128. The patch 120 may be replenished daily orat even longer intervals, to prolong the effective life of the patch. Insome embodiments, a single patch might be retained in place for days oreven months.

Moreover, by allowing indicia 132-138 to change color, or otherwisechange appearance after application of the bioactive agent, a patient 22would have a clear visual indicator or reminder as to whether or not acertain dosage had been administered. Alternatively, indicia 132-138 maybe color coded, or otherwise provided with indicia displayed on thevarious fluid reservoirs 50-56. For example, each indicium may be acolor that corresponds to a color of a fluid reservoir 50, 52, 54 or 56,or a distinctive shape cut in a release layer on top of pad 120, such asthe letters A, B, C and D, each of which may correspond to a particularfluid reservoir. An external surface of each reservoir can also beprovided with identifiers, such as bar codes, that are recognized by anoptical sensor in the dispenser, to assure that the correct prescribedagent it being dispensed from each reservoir.

Furthermore, while the illustrated applicator 30 has been shown as arather large box like device capable of dispensing at least fourdifferent types of fluids, it is apparent that the configuration of thehousing may be simplified and modified to provide a more compact unit,particularly for application of a single fluid. Such a more compact unitmay easily be concealed within the palm of one's hand, allowing for morediscrete application of the composition, such as when a dosage isrequired while shopping, in a meeting, or otherwise in public,particularly if the patch is positioned in an accessible locationbeneath loose fitting clothing.

In use, transdermal patch 25 or 120 is applied to the skin of a subject22. Impermeable backing 28 is peeled away from patch 25, 120 andapplicator 20 is applied to the patch, with spacers 36, 38 resting onthe skin. Applicator 20 is then actuated, either manually by pressingswitch 102 or automatically by sensors in applicator 20, to apply abioactive agent from applicator 20 to patch 25, 120. This applicationcan occur several times a day, or at longer intervals. The applicatormay be programmed to remind the user (for example by an audible beep) touse the applicator to replenish the supply of drug in the patch 25, 120.

Embodiment of FIGS. 5-7

An example of a more compact dispenser 200 is shown in FIGS. 5-7, inwhich the dispenser applies a bioactive agent directly to the skin of asubject, without the necessity of an intervening patch. Dispenser 200 isapplied to forearm 202 of a subject to whom a bioactive substance is tobe administered. In the illustrated example, dispenser 200 is retainedin place by a strap 204 which wraps around forearm 202. An elastomericseal 205 extends around the base of dispenser 200, to simultaneously actas a spacer and form a substantially closed chamber between the ejectionhead and the skin. Although dispenser 200 is shown attached to an arm202, it may also be applied to many other parts of the body (such as thetorso or leg) which have sufficient permeability to receive thebioactive agent. Many different attachment devices can also besubstituted for the strap 204, such as a suction device or adhesive. Forexample, a relative vacuum can be created within seal 205 to holddispenser 200 in place, for instance if the seal is formed to act as asuction cup device.

Dispenser 200 includes a removable, replaceable, and/or refillablemodule 206, which includes a container 208 and an enlarged endplate 210(or other means to facilitate removal) which may be grasped tomanipulate, insert and remove module 206 from dispenser 200. Asparticularly shown in FIG. 6, container 208 has an upper storage chamber212 for holding a bioactive liquid (such as a drug), and a lowerpiezoelectric dispenser portion 214 that includes an array ofpiezoelectric chambers 215 that communicate with storage chamber 212through small openings 216. Droplet orifices are also provided throughthe lower face of dispenser 200, as shown in FIG. 7, to form an array ofdispenser orifices 218. At least a portion of one or more walls of eachchamber is a piezoelectric member that expands when electrical currentis passed through it. The chambers 215 are sufficiently small so thatliquid supplied to the chambers 215 from storage chamber 212 remains ineach of the chambers 215 (for example by surface tension or backpressure) until the liquid is expelled as a droplet by the expansion ofthe piezoelectric member. Expansion of the piezoelectric member reducesa volume of the chamber 215 to expel a carefully regulated volume of theliquid.

A controller 220, such as one in the form of a programmable microchip,is attached to an interior wall of dispenser 200. Information may bepre-programmed into controller 220, or controller 220 may be activatedby pressing a switch 222 on the exterior of dispenser 200.Alternatively, controller 220 may be programmed by a computer (notillustrated) which communicates with controller 220 through a port (notillustrated) on the exterior of dispenser 200. Controller 220 is capableof selectively activating different piezoelectric members to expelliquid from each chamber, and may also precisely modulate a volume ofliquid that is expelled, by regulating a drive signal that passesthrough the piezoelectric member. Controller 220 may also communicatewith one or more remote bio-sensors which monitor one or more parametersof a subject's condition, such as a pulse oximetry device 224 (FIG. 5)shown clipped on a finger of the subject. The pulse oximetry device 224may provide information about pulse rate and blood oxygenation levels tocontroller 220 by an electrical lead (not illustrated) or other remotecommunication device, such as infrared or radiowave communication.

In operation, module 206 is placed in dispenser 200, and dispenser 200is applied to the skin of the subject and secured in place by latchingstrap 204 around forearm 202. The elastomeric seal 205 provides asubstantially liquid impermeable seal that helps form a closed chamberbetween dispenser 200 and the skin. Switch 222 is then depressed toactivate controller 220, which sends one or more electrical signals toselected piezoelectric members to change shape or other feature aselected number of times, and induce a vibration that discharges one ormore droplets of liquid from corresponding piezoelectric chambers 215.The pattern of discharge may be controlled by selectively activatingdifferent piezoelectric members, but in one embodiment all thepiezoelectric members are simultaneously activated to expel smalldroplets from all of dispenser orifices 218. Very small liquid dropletsizes may be dispensed in this manner to provide a fine mist of dropletsthat adhere to the skin, for example by surface tension. The appliedliquid then moves through the skin by transdermal flux, to deliver abioactive agent.

Expulsion of liquid droplets may be repeated at selected intervals, forexample every few seconds, minutes, hours or days, to provide aconcentration gradient of the drug on the skin surface sufficient toprovide transdermal flux across the cutaneous barrier. Generally, theamount of liquid applied is not sufficient to causing a pooling ofliquid on the surface of the skin, although such pooling is certainly anoption in some embodiments. In this manner, the dispenser can replace atransdermal patch 25, 120, which avoids problems of patch degradationand dislodgment (for example caused by bathing or sweating). Dispenser200 effectively becomes an electromechanical patch that may in someembodiments be removed for short periods (such as for bathing) andreplaced, unlike traditional patches which degrade or becomenon-adhesive following prolonged use or exposure to moisture. Dispenser200 may also provide very prolonged administration of a drug, for days,weeks, months, or even years. All that is required is that module 206 bereplaced or refilled when depleted.

The electromechanical patch may also be programmed to administermultiple different drugs at different times. In such an embodiment,module 206 may contain multiple liquid sub-compartments that containdifferent drugs to be administered. The different sub-compartmentssupply different liquids to different piezoelectric chambers 215, whichcan be selectively activated to dispense different drugs eithersimultaneously or at different times. Patients who require complex drugregimens, for example taking multiple different drugs at many differenttimes of day, will benefit from the ability of controller 220 to trackand administer the drugs. Moreover, controller 220 may be repeatedlyreprogrammed as pharmaceutical dosage regimens are changed in responseto a changing medical condition of a subject. Dosage regimens may evenbe automatically and/or remotely changed in response to varying clinicalparameters, such a the results of laboratory tests.

The electromechanical patch 200 provides even greater versatility forsubstantially immediately responding to the changing medical status ofthe wearer. Sensors applied to the subject, such as pulse oximetrysensor 224 (FIG. 5), may provide real time feedback to the controller220 to alter dosage regimens. For example, if one of the drugs to bedispensed is clonidine (which reduces adrenergic stimulation), thensensor 224 provides continuous feedback about pulse rate, which oftencorrelates with a degree of adrenergic stimulation. In a clinicallycorrect situation, the dosage of clonidine administered may becorrelated to the pulse rate detected by sensor 224, such that thedosage is increased as pulse rate rises and decreased as pulse ratedeclines. Alternatively, if the medication being dispensed is an opiateanalgesic that has a potential adverse effect on respiratory rate, thenfurther administration of the drug would be halted if blood oxygenationlevels fall below a predetermined value, for example 94%.

Although the electromechanical patch dispenser 200 has been described asa substitute for a conventional transdermal patch, it may also be usedin conjunction with such a patch 25, 120. In such an embodiment,dispenser 200 is used to apply drug to the patch 25 or 120, whichretains the drug against the skin until transdermal flux of the drugoccurs. Drug in the patch may be repeatedly replenished by dispenser200.

In yet other embodiments, the dispenser may be an iontophoreticdispenser, in which ionized drugs are moved through the skin under theinfluence of an applied electric current. Alternatively, drug movementthrough the skin can be enhanced by phonophoresis or sonophoresis, inwhich drug molecules are moved through the skin under the influence ofsonic energy, such as ultrasound waves applied to the cutaneous target.Iontophoretic and phonophoretic drug delivery are disclosed in greaterdetail in Remington: The Science and Practice of Pharmacy at page 1584.

While the illustrated embodiment of applicator 200 is shown as beingattached to the subject by the strap 204, in other implementations itmay be more advantageous to have the applicator 200, perhaps in asmaller or disposable form, attached to the subject by an adhesive tape,for instance under a blouse or a shirt for discrete use. As mentionedabove, the applicator 200 may be coupled to a remote sensor, or mayinclude a sensor, such as the optical sensor 48 of FIG. 3, or amechanical sensor, as mentioned briefly above. For example, a mechanicalsensor such as an accelerometer 225 may be used, for instance to monitorphysical parameters of a subject, such as a mechanical sensor positionedto monitor heartbeats, breathing forshortness-of-breath/excessively-fast-breathing, or, in a more practicaldaily application, to monitor a subject's activity. For instance, thosejogging or involved in playing sports may need a boost of medicationover the dosage used when they are working at a desk, watchingtelevision, or sleeping, with the mechanical accelerator sensor 225monitoring the change in inertia of the individual (bouncing more whenactive). In response to increased activity signals generated by themechanical sensor 225, the controller 220 in most instances, administersmore medication during these periods of increased activity.

In other embodiments, the applicator 200 may be activated by depressingthe button or switch 222, or additional switches, for instance inresponse to an event to administer an additional dosage or a boosterdosage. In such an implementation, the button 222 may be labeled withthe event or symptom for which the booster dose is required. Forexample, the button 222 may be labeled “pain” for addressing painsymptoms, such as chest pains, headaches or nausea, or perhaps “relief”may be a more optimistic label. Examples of events may be eating,strenuous physical activity such as manual labor, playing sports orjogging. Indeed, several buttons may be provided to indicate a varietyof events, each of which may administer different dosages or types ofmedication. As another example, the bioactive composition may not onlybe one to treat a symptom, but for various physical events, thebioactive composition may be a performance enhancing composition, suchas one designed to provide a boost of energy.

Embodiment of FIG. 8

FIG. 8 shows another embodiment of a transdermal application system 300,constructed in accordance with the present invention, for applying abioactive substance or agent 301 to a skin surface 302 of a subject orpatient 304, preferably using a patch 305, which may be constructed asdescribed above for patch 25. The bioactive agent 301 is stored in aremote reservoir, here shown as a flexible bladder 306, such as aplastic bag similar or identical to the containers which are used toadminister intravenous (“IV”) fluids to patients in hospitals,ambulances, nursing homes, and the like. The illustrated container 306preferably includes a fixture, such as eyelet 308, which may be used tohang the container from a conventional IV stand, allowing easysubstitution of the system 300 for conventional IV's.

The transdermal application system 300 illustrated in FIG. 8 includes anapplicator or dispenser 310, which may be constructed as described abovefor applicators 30 and 200. The applicator 310 in FIG. 8 shows one formof the internal workings of thermal fluid ejecting system, similar tothat used in thermal inkjet printheads in the printing arts, forinstance of the construction described in U.S. Pat. No. 5,420,627, whichis assigned to the present assignee, Hewlett-Packard Company. Theapplicator 310 includes a main body 312 that defines a feed chamber 314,which receives the bioactive fluid 301 (labeled “bioagent” in FIG. 8)from the ink reservoir 306 by way of a fluid conduit, such as tubing315, illustrated partially schematically in FIG. 8. A fluid ejectionmechanism 316 is preferably located centrally within the chamber 314,and held in place through attachment by an adhesive or other bondingagent to a flexible polymer tape 318, such as Kapton® tape, availablefrom the 3M Corporation, Upilex® tape, or other equivalent materialsknown to those skilled in the inkjet arts. The illustrated tape 318serves as a nozzle orifice plate by defining at least one, butpreferably more, fluid ejection nozzle hole or orifice 320 formed intape 318 by, for example, laser ablation technology. The adhesivebetween the body 312 and the tape 318 may be of an epoxy, a hot-melt, asilicone, a UV curable compound, mixtures thereof, or their structuralequivalents.

The ink ejection mechanism 316 includes a silicon substrate 322 thatcontains for each nozzle 320 an individually energizable thin filmfiring resistor 324, each located generally behind an associated singlenozzle 320. The firing resistors 324 act as ohmic heaters whenselectively energized by one or more enabling signals or firing pulses325, which are delivered from a controller 326 through conductors(omitted for clarity) carried by the polymer tape 318. The controller326 may operate as described above for controllers 100 and 220 of FIGS.1 and 5. In the illustrated embodiment of FIG. 8, the controller 326receives a patient condition input signal 328 from a patient monitoringdevice 330, which may be a remote bio-sensor monitoring one or moreparameters of a subject's condition, similar to the pulse oximetrydevice 224 of FIG. 5, or a conventional hospital patient monitoringdevice for gathering information concerning a patient's blood pressure,oxygen level, respiration, etc.

The ink ejection mechanism 316 also includes a barrier layer 332 whichmay be formed on a surface of the substrate 322 using conventionalphotolithographic techniques. The barrier layer 332 may be a layer ofphotoresist or some other polymer, which in cooperation with tape 318defines a vaporization chamber 334 surrounding an associated firingresistor 324. The barrier layer 332 is bonded to the tape 318 by a thinadhesive layer, such as an uncured layer of polyisoprene photoresist.Fluid 301 from the feed chamber 314 flows through one or more feedchannels 336, around the edges of the substrate 322, and into thevaporization chamber 334. When the firing resistor 324 is energized,fluid 301 within the vaporization chamber 334 is ejected, as illustratedby an emitted bioactive fluid droplet 338. In the illustratedembodiment, the fluid droplet 338 is shown traveling through an air gapbetween the orifice plate tape 318 and the patch 305, with this air gapbeing defined by spacer members, such as spacers 340 and 342 shownextending from the applicator body 312, for instance in the same manneras described above for spacers 36 and 38 in FIGS. 1-3. Alternatively, anelastomeric lip, such as lip 205 in FIG. 5, may be used instead ofspacers 340 and 342, with or without the patch 305.

In operation, the dispenser 310 supplies accurate, metered doses of thebioactive fluid 301 received via tubing 315 at intervals (such ascontrolled or selected intervals) to the patch 305 when used. The patch305 absorbs the fluid 301 and retains the fluid against the patient'sskin 302 to achieve transcutaneous delivery of the bioactive liquid 301.In this manner, long term administration of the agent 301 to the patch305 may be achieved, without the necessity of repeatedly applying adispenser to the patch.

The transdermal application system 300 illustrated in FIG. 8 isparticularly suitable for drug administration in a hospital, clinic, orother health care delivery facility in which medication is administeredfor a prolonged period to a subject. Furthermore, anyone who has had anIV knows it is painful to have a needle inserted into their vein,followed by the pain and annoyance of dealing with the needle remainingtaped to their hand while the IV fluid is administered. Emergencymedical personal often have to deal with trying to insert an IV needleinto a trauma patient with low blood pressure, where locating a viablevein is often difficult. Medical personal treating the elderly or infirmoften encounter the same difficulties, with their patients suffering thepain of the needle probing for a vein. Clearly, the transdermalapplication system 300 alleviates these problems for both patients andmedical personal alike by providing a non-invasive method ofadministering medications or other bioactive agents.

Embodiment of FIG. 9

FIG. 9 shows an alternate embodiment a transdermal application systemusing the applicator 200 of FIG. 5, for instance, in conjunction with abioactive composition attracting agent, such as a cream, a paste, or asalve 400 applied to the skin 402 of a subject 404, here on a skinblemish, such as a wart 405. The applicator 200 is shown by way ofillustration, and it is apparent that applicators 30 and 310 may also beused with cream 400, shown here without use of a patch 25, 120, 305.Here we see the applicator 200 ejecting bioactive fluid droplets 406into a chamber 408 defined between the ejection head defining nozzles218 (see FIGS. 6 and 7), the patient's skin 402, and the sealing lip205. The droplets 406 accumulate in a puddle 406′ which is drawn towardthe wart 405 as indicated by arrows 408, 410 by the fluid's affinitywith the cream 400. The fluid 406′ and the cream 400 mix together so thefluid travels through the cream to contact and treat the wart 405. Inthis manner, the bioactive-agent-attracting cream 400 assists in drawingor pulling the treatment fluid 408 toward the location to be treated,here, wart 405. Examples of bioactive-agent-attracting creams, pastes orsalves include a product sold under the trade name Recepta-gel®, as wellas dimethyl sulfoxide (“DMSO”). Such a bioactive composition attractingagent 400 may also enhance the penetration of the bioactive composition406′, for instance, in the same manner as DMSO or glycerin works toenhance transcutaneous flux of the bioactive agent 406′ that isdelivered to wart 405. Thus, when provided as a refill kit, the a freshmodule carrying the treatment fluid 406 may be supplied with a containerof the cream 400, for instance in a tear-away container(s), similar tothose in which single servings of mustard and ketchup are supplied, orin a resealable tube.

CONCLUSION

Many other variations of devices and methods are within the scope ofthis disclosure. For example, instead of mixing a bioactive agent withanother agent (such as another bioactive agent, for example a penetrantsuch as DMSO) at the time of ejection from a jet dispenser, the agentscan be mixed prior to ejection (for example, as illustrated in U.S. Pat.No. 5,980,014 assigned to Sony Corporation). Also, instead of mixingbioactive agents prior to delivery, one of the bioactive agents can beapplied to the cutaneous surface, or the penetrant can be present in thepad itself. For example, DMSO or other agents can be applied to theskin, or can be present in the patch, to enhance transcutaneous flux ofa bioactive agent that is delivered to the skin or pad. Anothervariation uses the optical sensor 48 to read patient identification,such as a bar code on a patient's hospital identification bracelet, withthis patient information then being used by controller 100 to adjust thedosage and/or type of medication administered. Such a system avoidsaccidentally administering the wrong medication to a patient. As anotherexample, the embodiments shown in the drawings are given to illustratethe principles and concepts covered by the claims below, and it isapparent that the applicator may be constructed larger or smaller thanthose shown here.

This specification has described several detailed examples, which arenot intended to be limiting. Rather, these examples are provided toillustrate some of the embodiments which come within the scope of thefollowing claims.

1. An applicator for cutaneous delivery of a bioactive composition to acutaneous target, comprising: a jet dispenser comprising an orifice anda container which holds and delivers the bioactive composition to saidorifice for ejection therethrough; and a spacer positioned to elevatethe orifice above the cutaneous target such that an air gap isestablished that extends directly from the dispenser orifice to thecutaneous target, the bioactive composition traveling across the air gapbetween the dispenser orifice and the target during ejection of thebioactive composition to the target; a main body which supports saidcontainer; a dispensing head which supports said orifice; and a flexiblelink which couples together said main body and said dispensing head. 2.An applicator according to claim 1, wherein the spacer is supported bythe dispenser.
 3. An applicator according to claim 1, wherein the spaceris for attachment to the cutaneous target.
 4. An applicator according toclaim 1, further comprising an adhesive applicator patch for applicationto skin, wherein the adhesive applicator patch provides at least aportion of the cutaneous target.
 5. An applicator according to claim 1,further comprising an indicator which indicates a degree of depletion ofthe bioactive composition in the dispenser.
 6. An applicator accordingto claim 5, wherein said indicator comprises an indicator light.
 7. Anapplicator according to claim 1, further comprising a display whichdisplays information about said composition.
 8. An applicator accordingto claim 1, further comprising an interface which receives a memorystorage device containing dosage information concerning administrationof said composition.
 9. An applicator according to claim 1, furthercomprising a keypad input which receives dosage information concerningadministration of said composition.
 10. An applicator according to claim1, further comprising: a display which displays information about saidcomposition, including various dosages; and a keypad input includingscroll keys which when activated cause the display to selectively showsaid various dosages.
 11. An applicator according to claim 1, furthercomprising a controller which is programmable.
 12. An applicatoraccording to claim 11, wherein said controller is programmable from aremote computer in communication with said controller.
 13. An applicatoraccording to claim 1, wherein said flexible link is hollow and containsa fluid conduit which fluidically couples said container to saidorifice.
 14. An applicator according to claim 1, further comprising amain body which supports said container and said orifice.
 15. Anapplicator according to claim 14, wherein said container is removablefrom the main body.
 16. An applicator according to claim 1, furthercomprising a dermal patch configured to be interposed between saidorifice and skin, wherein the dermal patch provides said target.
 17. Anapplicator according to claim 16, wherein the dermal patch is of anabsorbent material which receives said delivery of said composition. 18.An applicator according to claim 1, wherein: the container comprisesplural containers; the jet dispenser comprises plural orifices, eachorifice being fluidically coupled to a respective container.
 19. Anapplicator according to claim 1, wherein the spacer comprises a pair ofspacer bars flanking the orifice on generally opposing sides of a paththat the bioactive composition travels from the orifice to the cutaneoustarget.
 20. An applicator for cutaneous delivery of a bioactivecomposition to a cutaneous target, comprising: a jet dispensercomprising an orifice and a container which holds and delivers thebioactive composition to said orifice for ejection therethrough; and aspacer positioned to elevate the orifice above the cutaneous target suchthat an air gap is established that extends directly from the dispenserorifice to the cutaneous target, the bioactive composition travelingacross the air gap between the dispenser orifice and the target duringejection of the bioactive composition to the target, wherein the spacercomprises a continuous elastomeric seal that selectively substantiallyseals the dispenser against the target to form a substantially closedchamber when the dispenser is in contact with the target.
 21. Anapplicator according to claim 20, wherein the applicator is anapplicator for transdermal delivery of a bioactive composition capableof transdermal flux.
 22. An applicator according to claim 20, furthercomprising a bioactive composition in the container.
 23. An applicatoraccording to claim 22, wherein the bioactive composition is apharmaceutical composition.
 24. An applicator according to claim 23,wherein the pharmaceutical composition is capable of transdermaldelivery.
 25. An applicator according to claim 20, further comprising acontroller which automatically ejects the bioactive composition from thedispenser orifice at selected times.
 26. An applicator according toclaim 25, wherein the controller is a microprocessor programmed todispense the bioactive composition at predetermined intervals.
 27. Anapplicator according to claim 20, further comprising an attachmentmember for selectively retaining the dispenser in prolonged contact withthe cutaneous target.
 28. An applicator according to claim 27, whereinthe attachment member comprises a strap.
 29. An applicator according toclaim 27, wherein the attachment member comprises an adhesive.
 30. Anapplicator according to claim 20, further including a reservoircontaining said bioactive composition and a fluid conduit to convey thebioactive composition from the reservoir to the jet dispenser.
 31. Anapplicator according to claim 30, wherein said fluid conduit comprisestubing.
 32. An applicator according to claim 30, wherein said reservoircomprises a collapsible bladder.
 33. An applicator according to claim20, wherein the jet dispenser comprises plural orifices, eachfluidically coupled to the container.
 34. An applicator according toclaim 20, wherein the cutaneous target faces the dispenser orificeduring ejection of the bioactive composition to the target.
 35. Anapplicator for cutaneous delivery of a bioactive composition to acutaneous target, comprising: a jet dispenser comprising an orifice anda container which holds and delivers the bioactive composition to saidorifice for ejection therethrough, wherein the container comprisesmultiple container modules, and at least two of the container modulescontain different bioactive substances that combine after ejection toproduce a bioactive effect; and a spacer positioned to elevate theorifice above the cutaneous target such that an air gap is establishedthat extends directly from the dispenser orifice to the cutaneoustarget, the bioactive composition traveling across the air gap betweenthe dispenser orifice and the target during ejection of the bioactivecomposition to the target.
 36. An applicator according to claim 35,wherein the multiple container modules are removable from the dispenser.37. An applicator according to claim 35, wherein at least one of thecontainer modules contains bioactive agent in powder form.
 38. Anapplicator according to claim 35, wherein at least one of the bioactivesubstances is a penetration enhancer that improves cutaneous penetrationof another bioactive substance.
 39. An applicator according to claim 38,wherein the penetration enhancer is dimethyl sulfoxide (DMSO).
 40. Anapplicator according to claim 35, wherein the bioactive composition is anitrate, an anti-hypertensive drug, an analgesic, a hormone or ananalogue thereof, or nicotine or an analogue thereof.
 41. An applicatoraccording to claim 40, wherein the anti-hypertensive drug is clonidineor minoxidil, the analgesic is fentanyl, or the hormone is estrogen ortestosterone.
 42. An applicator for cutaneous delivery of a bioactivecomposition to a cutaneous target, comprising: a jet dispensercomprising an orifice and a container which holds and delivers thebioactive composition to said orifice for election therethrough; aspacer positioned to elevate the orifice above the cutaneous target suchthat an air gap is established that extends directly from the dispenserorifice to the cutaneous target, the bioactive composition travelingacross the air gap between the dispenser orifice and the tarciet duringejection of the bioactive composltion to the target; a bio-sensor whichmonitors a parameter of a subject and generates a signal in responsethereto, wherein the bio-sensor comprises a pulse oximetry device; and acontroller which automatically dispenses the bioactive composition fromthe dispenser orifice in response to said signal.
 43. An applicatoraccording to claim 42 wherein said parameter comprises pulse rate. 44.An applicator according to claim 42 wherein said parameter comprisesblood oxygenation levels.
 45. An applicator according to claim 42wherein said bio-sensor communicates said signal to the controller byinfrared communication.
 46. An applicator according to claim 42 whereinsaid bio-sensor communicates said signal to the controller by radiowavecommunication.
 47. An applicator for cutaneous delivery of a bioactivecomposition to a cutaneous target, comprising: a jet dispensercomprising an orifice and a container which holds and delivers thebioactive composition to said orifice for ejection therethrough; and aspacer positioned to elevate the orifice above the cutaneous target suchthat an air gap is established that extends directly from the dispenserorifice to the cutaneous target, the bioactive composition travelingacross the air gap between the dispenser orifice and the target duringejection of the bioactive composition to the target; an optical sensor;and a controller in communication with said sensor; wherein said targetchanges color following delivery of the bioactive composition, and saidoptical sensor detects said color change and in response thereto, thecontroller ceases ejection of said composition.
 48. An applicator forcutaneous delivery of a bioactive composition to a cutaneous target,comprising: a jet dispenser comprising an orifice and a container whichholds and delivers the bioactive composition to said orifice forejection therethrough; and a spacer positioned to elevate the orificeabove the cutaneous target such that an air gap is established thatextends directly from the dispenser orifice to the cutaneous target, thebioactive composition traveling across the air gap between the dispenserorifice and the target during ejection of the bioactive composition tothe target; an optical sensor; and a controller in communication withsaid sensor; wherein said target changes color following absorption ofthe bioactive composition, and said optical sensor detects said colorchange and in response thereto, the controller causes said orifice toeject said composition.
 49. An applicator for cutaneous delivery of abioactive composition to a cutaneous target, comprising: a jet dispensercomprising an orifice and a container which holds and delivers thebioactive composition to said orifice for ejection therethrough; and aspacer positioned to elevate the orifice above the cutaneous target suchthat an air gap is established that extends directly from the dispenserorifice to the cutaneous target, the bioactive composition travelingacross the air gap between the dispenser orifice and the target duringejection of the bioactive composition to the target an optical sensor;and a controller in communication with said sensor; wherein thecontainer comprises two container modules each containing differentbioactive substances, the target has indicia detectable by said opticalsensor indicative of one of said different bioactive substances, and thecontroller causes said orifice to eject said one of said differentbioactive substances.
 50. An applicator for cutaneous delivery of abioactive composition to a cutaneous target, comprising: a jet dispensercomprising an orifice and a container which holds and delivers thebioactive composition to said orifice for ejection therethrough; and aspacer positioned to elevate the orifice above the cutaneous target suchthat an air gap is established that extends directly from the dispenserorifice to the cutaneous target, the bioactive composition travelingacross the air gap between the dispenser orifice and the target duringejection of the bioactive composition to the target; plural activationdevices which may be manually triggered to elect said bioactivecomposition from the jet dispenser, each activation device bearing alabel corresponding to an event, with different dosages of the bioactivecomposition being ejected from the jet dispenser according to which ofthe plural activation devices is triggered.
 51. An applicator forcutaneous delivery of a bioactive composition to a cutaneous target,comprising: a jet dispenser comprising an orifice and a container whichholds and delivers the bioactive composition to said orifice forelection therethrough, wherein the jet dispenser contains pluralbioactive compositions; and a spacer positioned to elevate the orificeabove the cutaneous target such that an air gap is established thatextends directly from the dispenser orifice to the cutaneous target, thebioactive composition traveling across the air gap between the dispenserorifice and the target during ejection of the bioactive composition tothe target; and plural activation devices which may be manuallytriggered to eject said bioactive composition from the jet dispenser,with different bioactive compositions being ejected from the jetdispenser according to which of the plural activation devices istriggered.